POS1531 GUSELKUMAB, AN IL-23P19 SUBUNIT–SPECIFIC MONOCLONAL ANTIBODY, BINDS CD64+ MYELOID CELLS AND POTENTLY NEUTRALISES IL-23 PRODUCED FROM THE SAME CELLS
Authors: D. Mcgonagle, R. Atreya, M. Abreu, J. Krueger, K. Eyerich, K. Sachen, C. Greving, D. Hammaker, P. Bao, E. Lacy, I. Sarabia, J. Deming, M. Elloso, C. T. Ritchlin, I. Mcinnes, M. Allez, A. Fourie
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Monoclonal antibodies targeting the interleukin (IL)-23p19 subunit are effective in the treatment of psoriatic disease but have different molecular attributes that may translate to differences in clinical efficacy. Within this class, guselkumab (GUS) is a fully human IgG1 monoclonal antibody with a native Fc region, while risankizumab (RIS) is a humanised IgG1 antibody with a mutated Fc region. Binding of these therapeutic antibodies to Fcγ receptor (FcγR) I, also known as CD64, is of interest, as CD64<sup>+</sup> IL-23-producing myeloid cells are increased within inflamed tissue of patients with psoriatic disease <sup>[1]</sup>. Furthermore, the incidence and prevalence of psoriatic arthritis increases with the severity of psoriasis <sup>[2]</sup>, and joint disease activity is positively correlated with frequency of peripheral CD64<sup>+</sup> monocytes <sup>[3]</sup>. <h3>Objectives</h3> Functional characteristics of the antigen-binding and Fc regions of GUS and RIS were compared. <h3>Methods</h3> IL-23 binding affinity was evaluated <i>in vitro</i> using a kinetic exclusion assay (KinExA) and surface plasmon resonance. <i>In vitro</i> cellular potency was measured by impact on IL-23-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in human peripheral blood mononuclear cells. Binding of GUS and RIS to FcγRs was assessed in cells transfected with individual FcγRs. Primary human "inflammatory" monocytes differentiated with granulocyte-macrophage colony-stimulating factor and interferon-γ (IFN-γ) were induced to produce IL-23 via toll-like receptor stimulation and used to assess binding of GUS and RIS to CD64 and potential capture of endogenously secreted IL-23 by flow cytometry. The potential for GUS binding to CD64 on IFN-γ primed monocytes to trigger activation was assessed using a 41-plex cytokine bead assay. <h3>Results</h3> GUS and RIS displayed comparable picomolar binding affinity for IL-23 and equivalent high potency for inhibiting IL-23-induced STAT3 phosphorylation. GUS showed strongest binding to CD64 compared with other FcγRs, whereas RIS had negligible binding to any FcγR. GUS, but not RIS, showed dose-dependent Fc-mediated binding to CD64 on primary human "inflammatory" monocytes. Moreover, CD64-bound GUS was able to simultaneously capture IL-23 endogenously secreted from the same cells (<b>Figure 1</b>). GUS binding to CD64 on monocytes did not induce cytokine production. <h3>Conclusion</h3> GUS, but not RIS, simultaneously binds CD64<sup>+</sup> myeloid cells via its Fc region and neutralises IL-23 with high affinity and potency. Our <i>in vitro</i> data suggest a mechanistic benefit through enrichment of GUS within inflamed tissue of patients with psoriatic disease, where CD64<sup>+</sup> IL-23-producing myeloid cells are increased, such that GUS potently neutralises IL-23 at its source of production. These findings may contribute to differences in clinical-therapeutic profiles between antibodies. <h3>References</h3> [1]Mehta, H. et al. <i>J Invest Dermatol</i>. 2021;141:1707-1718. [2]Merola, J. et al. <i>J Am Acad Dermatol</i>. 2022;86:748-757. [3]Matt, P. et al. <i>Scand J Rheumatol</i>. 2015;44:464-73. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Dennis McGonagle Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Raja Atreya Consultant of: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Ferring, Fresenius Kabi, Galapagos, Gilead, GlaxoSmithKline, InDex Pharmaceuticals, Janssen, Kliniksa Pharmaceuticals, Merk Sharp &amp; Dohme, Novartis, Pfizer, Roche, Samsung Bioepsis, Stelic, Sterna Biologicals, Takeda, and Tillotts, Maria Abreu Consultant of: Prometheus Bioscience, Takeda, Pfizer, Janssen, Focus Medical Communications, Boehringer Ingelheim, Gilead, Imedex, Cornerstone Health, Landos Biophama, UCB, Eli Lilly, Bristol Myers Squibb, Arena Pharmaceuticals, and Cosmo Pharmaceuticals, Grant/research support from: Prometheus Bioscience, Takeda, Pfizer, Janssen, Focus Medical Communications, Boehringer Ingelheim, Gilead, Imedex, Cornerstone Health, Landos Biophama, UCB, Eli Lilly, Bristol Myers Squibb, Arena Pharmaceuticals, and Cosmo Pharmaceuticals, James Krueger Consultant of: AbbVie, Aclaris, Allergan, Almirall, Amgen, Arena, Aristea, Asana, Aurigene, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Escalier, Galapagos, Janssen, Eli Lilly, MoonLake Immunotherapeutics, Nimbus Lackshmi, Novartis, Pfizer, Sanofi, Sienna Biopharmaceuticals, Sun Pharma, Target-Derm, UCB, Valeant, and Ventyx, Grant/research support from: AbbVie, Akros, Allergan, Amgen, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Exicure Incyte, Innovaderm, Janssen, Kyowa Kirin, Eli Lilly, Nimbus Lackshmi, Novan, Novartis, Parexel, Pfizer, Regeneron, UCB, and Vitae Pharmaceuticals, Kilian Eyerich Consultant of: AbbVie, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, LEO Pharma, Eli Lilly, Janssen, Pfizer, Novartis, Sanofi, and UCB, Kacey Sachen Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Carrie Greving Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Deepa Hammaker Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Phuc Bao Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Eilyn Lacy Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Indra Sarabia Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Janise Deming Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Merle Elloso Shareholder of: Johnson &amp; Johnson, Employee of: Janssen, Christopher T. Ritchlin Consultant of: UCB, AbbVie, Amgen, Lilly, Pfizer, Novartis, Gilead, and Janssen, Grant/research support from: UCB, AbbVie, Amgen, Lilly, Pfizer, Novartis, Gilead, and Janssen, Iain McInnes Shareholder of: Compugen, Evelo, and Causeway Therapeutics, Consultant of: Compugen, AstraZeneca, Bristol Myers Squibb, Amgen, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Roche, UCB, AbbVie, Cabaletta, Gilead, Pfizer, and Sanofi; Board member for: National Health Service Greater Glasgow and Clyde; Trustee of: Versus Arthritis, Grant/research support from: Compugen, AstraZeneca, Bristol Myers Squibb, Amgen, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Roche, UCB, AbbVie, Cabaletta, Gilead, Pfizer, and Sanofi, Matthieu Allez Speakers bureau: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Janssen, Eli Lilly, Ferring, Galapagos, Gilead, IQVIA, Novartis, Pfizer, Genentech/Roche, Takeda, and Tillotts, Consultant of: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Janssen, Eli Lilly, Ferring, Galapagos, Gilead, IQVIA, Novartis, Pfizer, Genentech/Roche, Takeda, and Tillotts, Grant/research support from: Janssen, Genentech/Roche, and Takeda, Anne Fourie Shareholder of: Johnson &amp; Johnson, Employee of: Janssen.